HucMSC-derived exosomes alleviate inflammatory bowel disease via upregulating FXR to suppress macrophage ferroptosis

Inflammatory bowel disease (IBD) is a chronic intestinal disorder characterized by excessive inflammation and intestinal damage. Known for its chronic and relapsing nature, IBD currently lacks curative pharmacological therapies. Herein, we investigated the therapeutic potential of human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Ex) in IBD and explored the underlying mechanisms. In vivo and in vitro experiments demonstrated that the administration of hucMSC-Ex significantly attenuated inflammatory levels and ameliorated associated disease symptoms in IBD models. Concurrently, hucMSC-Ex treatment effectively modulated bile acid dysregulation in the IBD condition, contributing to the restoration of intestinal metabolic homeostasis. Mechanistically, the protective effects of hucMSC-Ex were mediated through the upregulation of farnesoid X receptor (FXR) expression. FXR, a critical regulator of intestinal homeostasis, plays a pivotal role, particularly in bile acid metabolism. Elevated FXR expression further suppressed ferroptosis in macrophages, as evidenced by reduced lipid peroxidation, diminished oxidative stress, restored iron metabolism homeostasis, and normalized expression of ferroptosis-related markers (GPX4, ACSL4, MBOAT1). Collectively, our findings indicate that hucMSC-Ex alleviates IBD by activating FXR in macrophages, thereby inhibiting lipid peroxidation and reducing ferroptosis, ultimately mitigating inflammation and ameliorating intestinal damage. This offers the potential of a FXR-targeted therapeutic strategy based on exosomes for the treatment of IBD.